This ARRA Challenge Grant application addresses Broad Challenge Area (05) - Comparative Effectiveness Research and Specific Challenge Topic 05-AG-105 - Comparative Intervention Trials for Diseases and Syndromes of Aging Including Neurodegenerative Diseases. Cognitive decline in older age is associated with loss of independence, functional decline in activities of daily living, nursing home placement, and mortality. Whether cognitive declines occur universally as part of the normal aging process or are the result of subclinical disease activity in a subgroup of elders at-risk for developing Alzheimer's disease (AD) is a matter of scientific debate. At present, older age, family history (FH) of AD, and the presence of the APOE e4 allele are the best, if imperfect, predictors of future cognitive decline in non-demented individuals. Our preliminary studies indicate that functional MRI (fMRI), using a semantic activation task, differentiates cognitively intact elders at-risk for AD from those not at-risk and can predict future cognitive decline in otherwise healthy older individuals. Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, (1) there exist no published studies directly comparing the efficacy of CT to ET in improving cognitive function, (2) no study examining whether a combined treatment (CT+ET) would be superior to a single intervention (CT or ET alone), (3) neuropsychological testing, the primary outcome measure of intervention trials, does not provide information pertaining to the underlying neural changes that mediate cognitive improvement, and (4) interventions have been aimed at non-specific groups of elders rather than targeting elders at-risk for developing AD. To address these gaps in our knowledge, we propose a single specific aim, namely to conduct a 12-week, four-arm, randomized, controlled, clinical trial to compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control (AC), consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, ADL, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD based on a positive FH and APOE e4 status. This project will be the first to (1) compare the relative efficacy of CT, ET, and a combined intervention;(2) use functional neuroimaging to assess intervention efficacy;and (3) intervene in older individuals at risk for developing AD. The long-range goal is to evaluate effective, low-risk, and relatively inexpensive interventions for addressing cognitive decline, with enormous implications for containing costs associated with health-care delivery to the ever increasing aging population of the United States. PUBLIC HEALTH RELEVANCE: Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, we do not know the relative efficacy of CT and ET in improving cognitive function or whether a combined treatment (CT+ET) would be superior to a single intervention. We also do not understand the brain changes that mediate cognitive improvement or whether the treatments would work in healthy elders at-risk for developing Alzheimer's disease (AD). In this 12-week, randomized, clinical trial, we will compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control, consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, activities of daily living, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD. The overall goal is to evaluate the efficacy of low-risk and relatively inexpensive interventions for addressing cognitive decline in older age.